Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A /sodium butyrate‐induced and 5‐aza‐2′‐deoxycytidine‐induced PTEN upregulation

Pan, Lina; Matloob, Ammar F.; Du, Juan; Pan, Hong; Dong, Zhixiong; Zhao, Jingquan; Feng, Yu; Zhong, Yun; Huang, Baiqu; Lü, Jun

doi:10.1111/j.1742-4658.2009.07542.x

Cited by 85 publications

(75 citation statements)

References 45 publications

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“…Based on the current state of knowledge and our data, vitamin D supplementation may be considered as a preventative measure for decreasing the risk for developing autoimmune diseases and potentially as adjunctive therapy. Moreover, we here show that the protective effect of vitamin D involves epigenetic mechanisms-in particular, DNA methylation, which may provide a molecular basis for cellular memory that mediates long-term effects (67)(68)(69) and suggests potential for future combined therapies (50).…”

Section: Discussionmentioning

confidence: 73%

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Zeitelhofer

Adzemovic

Gomez-Cabrero

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS. Vitamin D deficiency is one of the most consistently reported environmental factor in the etiology of multiple sclerosis (MS) (5), a chronic inflammatory disease of the CNS characterized by autoimmune destruction of myelin, axonal loss, and brain atrophy (6). Increased risk of developing MS has been described in carriers of rare and common variants of the CYP27B gene (7, 8), which encodes the enzyme that catalyzes the last step in converting vitamin D to its active form, from 25(OH)D 3 to 1,25 (OH) 2 D 3 . These studies imply a causal role of low vitamin D in MS, which has recently been further supported by Mendelian randomization studies in two large cohorts demonstrating that three genetic variants that associate with serum 25(OH)D 3 levels also associate with the risk of developing MS (9). However, high levels of vitamin D have been associated not only with the reduced risk of developing MS (10, 11) but also with the reduced risk for relapses, new brain lesions, and subsequent disability (12, 13). Moreover, it has been described that increased levels of vitamin D can reduce serum levels of . Most of what is known about the immunological mechanisms of vitamin D in MS comes from the studies in its animal model, experimental autoimmune encephalomyelitis (...

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Section: Discussionmentioning

confidence: 73%

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Zeitelhofer

Adzemovic

Gomez-Cabrero

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…NaBu has been applied in cellular and molecular research (23,24), particularly in antitumor research (25)(26)(27)(28). It plays a vital role in vitamin D-induced apoptosis through PTEN upregulation, which has potential benefit in gastric cancer therapy (29). Furthermore, NaBu activates Notch1 signaling, reduces tumor markers (e.g.…”

Section: Discussionmentioning

confidence: 99%

Sodium butyrate restores ASC expression and induces apoptosis in LS174T cells

Zhang

Bai

Ren

et al. 2012

International Journal of Molecular Medicine

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Abstract. Sodium butyrate (NaBu) is a short-chain fatty acid (SCFA), which has been proposed as a potential anticancer agent. Apoptosis-associated speck-like protein (ASC) is a pro-apoptotic signaling factor that is subjected to epigenetic silencing in human cancers. Modulation by the aberrant methylation of CpG islands of ASC is a well-characterized epigenetic mechanism, and the methylation-induced silencing of ASC has been observed in several types of tumors. NaBu induces cell cycle arrest, markers of cell differentiation and apoptosis in colon cancer. NaBu promotes transcriptional activation by relaxing the DNA conformation and displays anti-proliferative and differentiating activity in a wide variety of cancers. Thus, we used NaBu to investigate the relationship between the status of cell proliferation and the re-expression of ASC in colon carcinoma LS174T cells. Our experiments determined ASC re-expression at the protein level using western blotting. In addition, we used reverse transcriptionpolymerase chain reaction to detect the expression levels of ASC mRNA and an MTT assay to detect the inhibitory rate of cell growth. The apoptosis rate was also detected for further validation of the re-expression of ASC. The results showed that ASC re-expression was significantly increased in the LS174 cells following NaBu treatment in a time-and dose-dependent manner. The expression of ASC also induced the apoptosis of LS174T cells. These results suggest that NaBu plays a role in the reactivation of ASC expression and that the latter promotes the apoptosis of LS174T cells.

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“…Pan et al[99] found that 1,25(OH) 2 D treatment promoted apoptosis in the undifferentiated gastric cancer cell line HGC-27 through a mechanism that depends upon VDR-mediated PTEN upregulation. PTEN is a tumor suppressor gene that negatively regulates the anti-apoptotic Akt signaling pathway.…”

Section: Effects Of 125(oh)2 D On Cell Proliferation and Apoptosismentioning

confidence: 99%

Vitamin D and cancer: a review of molecular mechanisms

Fleet

DeSmet

Johnson

et al. 2011

Biochemical Journal

331

279

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Synopsis The population-based association between low vitamin D status and increased cancer risk can be inconsistent but is now generally accepted. These relationships link low serum 25 hydroxyvitamin D levels to cancer while cell-based studies show that the metabolite 1,25 dihydroxyvitamin D is the biologically active metabolite that works through vitamin D receptor to regulate gene transcription. Here we review the literature relevant to the molecular events that may account for the beneficial impact of vitamin D on cancer prevention or treatment. This data shows that while vitamin D-induced growth arrest and apoptosis of tumor cells or their non-neoplastic progenitors are plausible mechanisms, other chemoprotective mechanisms are also worthy of consideration. These alternative mechanisms include enhancing DNA repair, antioxidant protection, and immunomodulation. In addition, other cell targets such as the stromal cells, endothelial cells, and cells of the immune system may be regulated by 1,25 dihydroxyvitamin D and contribute to vitamin D mediated cancer prevention.

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Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A /sodium butyrate‐induced and 5‐aza‐2′‐deoxycytidine‐induced PTEN upregulation

Cited by 85 publications

References 45 publications

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Sodium butyrate restores ASC expression and induces apoptosis in LS174T cells

Vitamin D and cancer: a review of molecular mechanisms

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